MX2014002125A

MX2014002125A - Treatment of symptoms associated with female gastroparesis.

Info

Publication number: MX2014002125A
Application number: MX2014002125A
Authority: MX
Inventors: Matthew J D Onofrio; David A Gonyer; Marilyn R Carlson
Original assignee: Evoke Pharma Inc
Priority date: 2011-08-25
Filing date: 2012-08-23
Publication date: 2014-10-17
Also published as: JP2019031551A; EP2747561B1; RU2014111070A; JP2014524478A; EP2747561A4; JP2018008979A; EP2747561A1; WO2013028882A1; DK2747561T3; ES2683042T3; JP6511492B2; RU2616520C2; CA2846340A1; PL2747561T3; PT2747561T; TR201811221T4; US20130217775A1; MX356317B; BR112014004418A2; CN103957707A

Abstract

Nasal formulations of metoclopramide are administered for the treatment of symptoms associated with female gastroparesis. Also provided are methods of treating symptoms of female gastroparesis with nasal metoclopramide.

Description

TREATMENT OF SYMPTOMS ASSOCIATED WITH FEMALE GASTROPARESIA The present application claims priority of United States provisional patents No. 61 / 583,447 filed January 5, 2012 and 61 / 527,563 filed August 25, 2011, each of which is incorporated herein by reference in its entirety BACKGROUND OF THE INVENTION Metoclopramide is approved in the United States in forms of oral solution, oral tablet, tablet that is dissolved orally and solution for injection. Little has suggested the use of metoclopramide nasally administered for the treatment of emesis or nausea (see U.S. Patent No. 4,624,965 issued November 25, 1986, which is incorporated by reference herein in its entirety. ) Psilogenis has suggested the nasal administration of metoclopramide for the treatment of delayed onset emesis (see U.S. Patent No. 5,760,086 issued June 2, 1998, incorporated herein by reference in its entirety). Lehman et al. have proposed to administer nasal formulations of metoclopramide for the treatment of gastroparesis (see U.S. Patent No. 6,770,262 issued August 3, 2004, incorporated herein by reference in its entirety). totality).

SUMMARY OF THE INVENTION Under the direction of the inventors, a clinical study of the efficacy of intranasal metoclopramide in patients with male and female gastroparesis was carried out. As a result of the clinical study, the inventors found that, despite the similarities in pharmacokinetics between women and men who received metoclopramide nasal, female gastroparesis responded positively to nasal metoclopramide compared with placebo, but not male gastroparesis. No previous study has observed any difference in response compared to placebo by metoclopramide between patients with female and male gastroparesis. Even taking into account known differences between men and women, such as differences in mean body weight and the frequency of manifestation of gastroparesis in both sexes, the difference in the response to metoclopramide nasal was statistically significant. Thus, the inventors have discovered that, at least at the doses administered in the study, the nasal administration of metoclopramide is effective in the treatment of symptoms associated with female gastroparesis, but not in the treatment of symptoms associated with male gastroparesis.

Thus, some embodiments described herein document relate to a method of treating female gastroparesis, which comprises administering to an human female an effective amount of metoclopramide or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of metoclopramide is oral, buccal, sublingual, intranasal, pulmonary, topical, transdermal, rectal or intravenous administration of metoclopramide to a human female. In some preferred embodiments, the administration of metoclopramide is intranasal administration to a human female. The effective amount of metoclopramide is ineffective in treating symptoms associated with male gastroparesis. In some embodiments, metoclopramide is administered at a daily dose of about 20 mg to 160 mg (e.g., 40 mg to 80 mg) of metoclopramide base per day. In some embodiments, the daily dose of metoclopramide is administered as 1 to 8 intranasal aliquots. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots of about 5 mg to 25 mg (eg, 10 mg to 20 mg) of metoclopramide base per aliquot. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots of about 10 mg of metoclopramide base per aliquot. In some particular embodiments, the intranasal aliquots are approximately equal. In some embodiments, each intranasal aliquot has a volume of approximately 25 μ? at 150 μ? . In some embodiments, each intranasal aliquot has a volume of approximately 50 μ? . In some embodiments, the daily dose of metoclopramide is administered as 3-8 aliquots of approximately 14 mg of metoclopramide base per aliquot. In some embodiments, each aliquot has a volume of about 25 μ? at 150 μ? . In some embodiments, each aliquot has a volume of about 70 μ ?. In some embodiments, the daily dose of metoclopramide is administered as 3 or 4 intranasal aliquots of approximately 20 mg of metoclopramide base per aliquot. In some particular embodiments, the intranasal aliquots are approximately equal. In some embodiments, each intranasal aliquot has a volume of approximately 50 μ? at 150 μ? . In some embodiments, the treatment of symptoms associated with gastroparesis in women includes treatment of symptoms associated with female diabetic gastroparesis.

Thus, some embodiments described herein refer to a composition for the treatment of symptoms associated with female gastroparesis, said treatment comprising administering to an human female an effective amount of metoclopramide or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of metoclopramide is oral, buccal, sublingual, intranasal, pulmonary, topical, transdermal, rectal or intravenous. In some preferred embodiments, the administration of metoclopramide is intranasal. The effective amount of intranasal metoclopramide is ineffective in treating symptoms associated with male gastroparesis. In some embodiments, metoclopramide is administered at a daily dose of about 20 mg to 160 mg (e.g., 40 mg to 80 mg) of metoclopramide base per day. In some embodiments, the daily dose of metoclopramide is administered as 1 to 8 intranasal aliquots. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots of about 5 mg to 25 mg (eg, 10 mg to 20 mg) of metoclopramide base per aliquot. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots of approximately 10 mg of metoclopramide base per aliquot. In some embodiments, each The intranasal aliquot has a volume of approximately 25 μ? at 150 μ? . In some embodiments, each intranasal aliquot has a volume of approximately 50 μ ?. In some embodiments, the daily dose of metoclopramide is administered as 3-8 aliquots of approximately 14 mg of metoclopramide base per aliquot. In some embodiments, each aliquot has a volume of about 25 μ? at 150 μ? . In some embodiments, each aliquot has a volume of about 70 μ? . In some embodiments, the daily dose of metoclopramide is administered as 3 or 4 intranasal aliquots of approximately 20 mg of metoclopramide base per aliquot. In some particular embodiments, the intranasal aliquots are approximately equal. In some embodiments, each intranasal aliquot has a volume of approximately 50 μ? at 150 μ? . In some embodiments, the treatment of symptoms associated with female gastroparesis includes treatment of symptoms associated with female diabetic gastroparesis. Some embodiments provide for the use of a composition described herein for the preparation of a medicament for the treatment of female gastroparesis, such as female diabetic gastroparesis.

Some embodiments described in this document provide a method of improving the quality of life of a subject afflicted with female gastroparesis, in which the female subject is receiving metoclopraraide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable derivative or salt thereof. Some embodiments described herein provide a method for the treatment of upper abdominal pain associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method for the treatment of nausea associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method for the treatment of meteorism associated with gastroparesis in a female subject receiving therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some Embodiments described herein provide a method for the treatment of early satiety associated with gastroparesis in a female subject receiving intranasal metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method for the treatment of vomiting associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method of treating vomiting stress associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method for the treatment of fullness sensation (inability to finish a meal) associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a quantity physiologically effective of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method for the treatment of appetite loss associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method for the treatment of stomach fullness associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. . Some embodiments described herein provide a method for the stomach treatment that is visibly larger associated with gastroparesis in a female subject receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. the same. Some embodiments described herein provide a method for the treatment of upper abdominal discomfort associated with gastroparesis in a female component receiving metoclopramide therapy, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt or derivative thereof. Some embodiments described herein provide a method for the treatment of two, three, four, five, six or more symptoms associated with female gastroparesis selected from upper abdominal pain, nausea, bloating, early satiety, vomiting, straining, feeling of fullness (inability to finish a meal), loss of appetite, stomach fullness, stomach that is visibly larger, abdominal discomfort, which comprises administering a physiologically effective amount of metoclopramide or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of metoclopramide is oral, buccal, sublingual, intranasal, pulmonary, topical, transdermal, rectal or intravenous administration to a human female. In some preferred embodiments, the administration of metoclopramide is intranasal administration of metoclopramide to a human female. In some embodiments, each of the above symptoms is treated in a female subject, but less than half are treated in male subjects at the same dosage. In some embodiments, each of the above symptoms is treated in a female subject, but three or less, preferably two or less, and in some embodiments one or less, are treated in male subjects at the same dosage. The effective amount of intranasal metoclopramide is ineffective in treating symptoms associated with male gastroparesis. In some embodiments, metoclopramide is administered at a daily dose of about 20 mg to 160 mg (e.g., 40 mg to 80 mg) of metoclopramide base per day. In some embodiments, the daily dose of metoclopramide is administered as 1 to 8 intranasal aliquots. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots of about 5 mg to 25 mg (eg, 10 mg to 20 mg) of metoclopramide base per aliquot. In some embodiments, the daily dose of metoclopramide is administered as 3-8 intranasal aliquots of approximately 10 mg of metoclopramide base per aliquot. In some embodiments, each intranasal aliquot has a volume of approximately 25 μ? at 150 μ? . In some embodiments, each intranasal aliquot has a volume of approximately 50 μ? . In some embodiments, the daily dose of metoclopramide is administered as 3-8 aliquots of approximately 14 mg of metoclopramide base per aliquot. In some embodiments, each aliquot has a volume of about 25 μ? at 150 μ? . In some embodiments, each aliquot has a volume of about 70 μ? . In some embodiments, the daily dose of metoclopramide is administered as 3 or 4 intranasal aliquots of approximately 20 mg of metoclopramide base per aliquot. In some particular embodiments, the intranasal aliquots are approximately equal. In some embodiments, each intranasal aliquot has a volume of approximately 50 μ? at 150 μ? . In some embodiments, the female gastroparesis treated is female diabetic gastroparesis. Some embodiments provide for the use of a composition described herein for the preparation of a medicament for the treatment of female gastroparesis, such as female diabetic gastroparesis.

Further embodiments, features and advantages will be apparent upon consideration of the following detailed description of the invention.

INCORPORATION BY REFERENCE All publications and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if specifically and individually indicate that each publication or individual patent application is incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing individual pharmacokinetic data, arithmetic mean and geometric mean after dose (blood plasma levels in ng / ml) at visits 3 and 7 during a clinical study for all patients receiving metoclopramide intranasal (IN) at 10 mg per dose and 14 mg per dose.

Figure 2 is a graph showing individual pharmacokinetic data, arithmetic mean and geometric mean after dose (blood plasma levels in ng / ml) at visits 3 and 7 of a clinical study for male and female patients receiving intranasal metoclopramide (IN) at 10 mg per dose and 14 mg per dose. No statistical difference was observed between men and women in the pharmacokinetic data (P).

Figure 3 is a graph showing total scores of mGCSI-DD means at the initial level and change from the initial level to week 4 in female subjects.

Figure 4 is a graph showing total mGCSI-DD mean scores at the initial level and change from the initial level to week 4 in male subjects.

DETAILED DESCRIPTION OF THE INVENTION The inventors have found that, despite the similarities in pharmacokinetics and demography among women and men who received metoclopramide nasal, intranasal administration of metoclopramide relieved symptoms associated with female gastroparesis, but not symptoms associated with male gastroparesis. Even taking into account known differences between women and men, such as differences in mean body weight and frequency of gastroparesis manifestation in both sexes, the difference in response to nasal metoclopramide was statistically significant. Thus, the inventors have found that, at least at the doses administered in the clinical study, the nasal administration of metoclopramide is effective in the treatment of symptoms associated with female gastroparesis, but not in the treatment of symptoms associated with male gastroparesis. Furthermore, it is the belief of the inventors that, given the similar pharmacokinetics demonstrated by male and female humans in intranasal studies, these results can be generalized to the treatment of gastroparesis, and in particular diabetic gastroparesis.

Thus, some embodiments described herein refer to a method for treating symptoms associated with female gastroparesis, which comprises administering to an human female an effective amount of metoclopramide or a pharmaceutically acceptable salt thereof. In some embodiments, the administration of metoclopramide is oral, buccal, sublingual, intranasal, pulmonary, topical, transdermal, rectal or intravenous. In some preferred embodiments, the administration of metoclopramide is intranasal. Some embodiments refer to the treatment of symptoms associated with female diabetic gastroparesis.

Thus, some embodiments described herein relate to a method of treating at least one, preferably two or more, symptoms of female gastroparesis, which comprises administering to an human female an effective amount of metoclopramide or a pharmaceutically acceptable salt thereof. . In some embodiments, the administration of metoclopramide is oral, buccal, sublingual, intranasal, pulmonary, topical, transdermal, rectal or intravenous. In some preferred embodiments, the administration of metoclopramide is intranasal. Some embodiments provided herein relate to a method of treating at least one, preferably two or more, symptoms of female gastroparesis selected from the group consisting of: nausea (feeling sick in the stomach as if to vomit); effort for vomit (have gagging as if he were going to vomit, but nothing gets); vomiting; fullness of the stomach; you can not finish a normal-sized meal; feeling excessively full after meals; loss of appetite; meteorism; stomach or belly visibly greater; and upper abdominal pain (above the navel); upper abdominal discomfort (above the navel). Some embodiments refer to a method of treating two, three, four, five, six, seven, eight, nine, ten or eleven of the symptoms selected from the group consisting of: nausea (feeling sick in the stomach as if it were going away) to vomit); effort to vomit (have gagging as if he were going to vomit, but nothing is achieved); vomiting; fullness of the stomach; you can not finish a normal-sized meal; feeling excessively full after meals; loss of appetite; meteorism; stomach or belly visibly greater; upper abdominal pain (above the navel); and upper abdominal discomfort (above the navel). In some embodiments, female gastroparesis is female diabetic gastroparesis.

As used herein, the term "female gastroparesis" refers to symptoms associated with gastroparesis experienced by human females.

As used herein, "metoclopramide" refers to metoclopramide in a solution formulation, which includes a salt of metoclopramide. In the quantification of the mass of metoclopramide herein, unless otherwise specified, all masses of metoclopramide refer to the mass of the free base, which has a molecular weight of 299.80. A method of manufacturing metoclopramide is described in US 3,177,252, which is incorporated herein by reference in its entirety.

An "effective amount" of metoclopramide (or a pharmaceutically acceptable salt thereof) is an amount of metoclopramide that is effective to provide statistically significant relief of one or more symptoms of gastroparesis in a cohort of human females. An "effective amount" is determined in comparison with the administration of placebo. In some embodiments, the efficacy is judged with reference to the cardinal symptom index of gastroparesis - Daily Agenda (GCSI-DD) and in some embodiments the efficacy is judged with reference to the modified GCSI-DD (mGCSI-DD), which is described in more detail in this document. An instrument for measuring additional symptoms is the Gastroparesis Symptom Assessment (GSA) that can be used to measure efficacy. Although not specifically measured in the referenced study, the GSA is derived from, and has similar statistical results, mGCSI-DD. See Example 1.

As provided herein, an effective amount of metoclopramide for the treatment of symptoms associated with female gastroparesis, such as female diabetic gastroparesis, is ineffective in treating symptoms associated with male gastroparesis. In some embodiments, metoclopramide is administered at a daily dose of about 20 mg to 60 mg of metoclopramide base per day. In some embodiments, the daily dose of metoclopramide is administered as 1 to 6 intranasal aliquots (e.g., sprays). In some embodiments, the daily dose of metoclopramide is administered as 4 intranasal aliquots. In some embodiments, the daily dose of metoclopramide is administered as 4 intranasal aliquots of about 5 mg to 15 mg of metoclopramide base per aliquot. In some embodiments, the daily dose of metoclopramide is administered as 4 intranasal aliquots of approximately 10 mg of metoclopramide base per aliquot. In some particular embodiments, the intranasal aliquots are approximately equal. In some embodiments, each intranasal aliquot has a volume of approximately 25 μ? at 150 μ ?. In some embodiments, each intranasal aliquot has a volume of approximately 50 μ? . In some embodiments, the daily dose of metoclopramide is administered as 4 aliquots of approximately 14 mg of metoclopramide base per aliquot. In some embodiments, each aliquot has a volume of about 25 μ? at 150 μ? . In some embodiments, each aliquot has a volume of about 70 μ? .

In some embodiments, the invention relates to nasal metoclopramide for the treatment of female gastroparesis, which is stable upon storage, especially long-term storage. The nasal solutions of metoclopramide are, in some embodiments, clear and / or colorless. Some embodiments herein provide for the use of nasal solutions of metoclopramide for the preparation of a medicament for the treatment of symptoms associated with female gastroparesis, such as symptoms associated with female diabetic gastroparesis.

In some embodiments described herein, a formulation of nasal metoclopramide and its use in the treatment of symptoms associated with female gastroparesis, comprising metoclopramide (or a pharmaceutically acceptable salt thereof), citrate buffer and benzalkonium chloride having a pH of at least approximately 5. In some embodiments, the nasal metoclopramide formulation is one described in the co-pending United States patent application together with the present 12 / 645.108 filed on December 22, 2009 (published as US 2010/0163032 on July 1 of 2010), which is incorporated in this document in its entirety.

Some embodiments described herein provide a manufacturing comprising a pharmaceutical composition of metoclopramide, for example, as described in co-pending United States patent application together with the present 12 / 645.108 filed on December 22, 2009 (published as US 2010/0163032 on July 1, 2010), which is incorporated herein in its entirety. In some embodiments, the means for nasal administration comprises a container containing the composition, a pump in fluid communication with the composition in the container and a nozzle in fluid communication with the pump, in which activation of the pump outputs a predetermined amount of said composition of the container and causes said predetermined amount of said composition to be expelled from said nozzle. In some embodiments, the predetermined amount of composition is approximately 10 μ? to approximately 200 μ ?, approximately 10 μ? at approximately 150 μ ?, approximately 50 μ? at approximately 150 μ ?, approximately 50 μ ?, approximately 55 μ ?, approximately 60 μ ?, approximately 75 μ ?, approximately 70 μ ?, approximately 75 μ ?, approximately 80 μ ?, approximately 85 μ ?, approximately 90 μ? approximately 95 μ ?, approximately 100 μ ?, approximately 110 μ ?, approximately 120 μ ?, approximately 125 μ ?, approximately 150 μ ?, approximately 175 μ? or approximately 200 μ? by activation ("spray" or "aliquot"). In order to combat the deleterious effects of light on metoclopramide, fabrication can conveniently include a container, especially an opaque container, ie, a container that is at least partially or completely insensitive to light. In some embodiments, a suitable opaque container will be brown or amber, especially brown or amber glass. In other embodiments, the opaque container will be an opaque polymer container, such as is commonly used in pharmaceutical techniques.

As used herein, the indefinite articles "a" and "an" mean "at least one", unless otherwise stated. Likewise, articles defined "the" and "the", unless otherwise indicated, mean "at least" if the context allows or demands that is of open ends.

As used herein, a "nasal delivery device" is a device that can deliver a dose of a composition comprising metoclopramide in the nose of a patient. In some embodiments, the nasal delivery device is an atomizer, comprising a container adapted to contain the metoclopramide solution and a pump adapted to draw a predetermined amount of the metoclopramide solution from the container dispensing the predetermined amount of metoclopramide solution to through a spray nozzle and in at least one nostril of a patient. Suitable nasal delivery devices are commercially available.

As used herein, the term "Spraying" indicates an atomized volume of fluid expelled from a nozzle of a nasal delivery device after a single activation of the nasal delivery device. In general, each spray is administered in a single nostril of a patient. As such, a "spraying", as used herein, is a type of "aliquot", the latter being a generic term with reference to a quantity of liquid sprayed, instilled or otherwise introduced into a liquid. nasal orifice of a subject, such as a patient.

As used herein, "metoclopramide" means metoclopramide (-amino-5-chloro-N- (2- (diethylamino) ethyl) -2-methoxybenzamide) or a pharmaceutically acceptable salt thereof, such as the salt of hydrochloride. If reference is made to a particular mass of metoclopramide, the mass cited is that of the free base of metoclopramide, unless otherwise specified.

As used herein, "oral" means a dosage form taken by mouth, such as a tablet, powder, soft gel capsule, hard gel capsule, tablet that is dissolved orally or thin film, liquid , etc.

Other terms used in this document have their recognized meanings in the matter, unless defined or described otherwise.

Formulation of nasal compositions of metoclopramide (use for the production of a medicine) The nasal compositions of metoclopramide can be manufactured for administration as a medicament for administration to a patient for one of the indications described herein. In some embodiments, the nasal metoclopramide formulation is one described in the co-pending United States patent application. with the present 12 / 645.108 filed on December 22, 2009 (published as US 2010/0163032 on July 1, 2010), which is incorporated herein in its entirety. Briefly, metoclopramide, buffer, benzalkonium chloride and optionally other components (such as sodium chloride or other osmolarity regulating agent, sorbitol or other sweetener, flavoring, etc.) can be prepared to some volume lower than the final target volume of the solution . The components can then be mixed until all the components are dissolved. Then, the pH can be adjusted, if necessary, by the addition of a suitable acid or base, such as HC1, NaOH, or the acid or base complementary to the buffer. Once the desired pH has been obtained, the solution can then be brought to the complete volume with water. The resulting solution can then be packaged in a container suitable for transport and distribution. In some embodiments, the suitable container includes a nasal pump as described in more detail below. In other embodiments, the suitable container may be a vial, such as an amber glass vial, which may be a glass ampoule, a glass bottle capped with an inert rubber stopper, and a folded top cap, or other suitable pharmaceutical vial.

Manufacture of nasal formulations Some embodiments described herein provide, as a manufacturing, a combination of a stable, clear and / or colorless solution of metoclopramide and a medium for intranasal administration of the metoclopramide solution. In some embodiments, the manufacture comprises one of the metoclopramide solutions described herein and an intranasal delivery device comprising a container, in which the metoclopramide solution is contained, a pump in fluid communication with the container and a nozzle in fluid communication with the pump. In use, the pump is activated by removing an amount of the metoclopramide solution from the container and expelling the solution out of the nozzle as an aerosolized spray. Suitable nasal delivery devices are commercially available. Among the nasal delivery device providers that may be combined with a stable, substantially clear and / or substantially colorless solution of metoclopramide according to the present invention may be mentioned Aptar (Valois of America, Congers, New York, and Pfeiffer of America, Princeton, NJ In some embodiments, the intranasal delivery device is partially or completely opaque, in order to protect the contents of the device from exposure to ambient light.

Procedures for treatment with nasally administered metoclopramide The nasal metoclopramide formulations described herein can be employed in methods for the treatment of symptoms associated with female gastroparesis.

In some embodiments provided herein, relief of symptoms associated with female gastroparesis is treated by intranasal instillation of a pharmaceutically effective amount of an intranasal metoclopramide solution. In some embodiments, the nasal metoclopramide is administered to female humans who have been diagnosed with gas clothing. In some embodiments, an effective dose of nasal metoclopramide is administered to a female patient for about 1 to about 12 weeks, about 1 to 8 weeks, about 5 weeks to about 12 weeks, about 5 to about 8 weeks, or about 1, 2. , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks.

In some embodiments, the effective daily dose of metoclopramide is about 20 mg / day to about 100 mg / day, which may be administered in 1 to 8, 1 to 6, 1 to 4 or 1 to 3 aliquots (e.g. "sprays") . In some embodiments, the daily dose of metoclopramide is about 40 mg / day to about 80 mg / day. In some embodiments in which the patient is renally insufficient or coadministered with a drug known to alter the metabolism or elimination of metoclopramide, the dose may be decreased by 25-75%, for example, at a daily dose of 20 mg , which can be administered in, for example, 4 aliquots of 5 mg each or 2 aliquots of 10 mg each. In some realizations, the daily dose administered to women is effective in female gastroparesis, but not in male gastroparesis. In some embodiments, the daily dose of metoclopramide nasal is about 30 mg / day to about 80 mg / day, administered in 1, 2, 3, 4, 5, 6, 7 or 8 aliquots. In some embodiments, the daily dose is 20, 22, 24, 25, 26, 28, 30, 32, 34, 35, 36, 38, 40, 42, 44, 45, 46, 48, 50, 52, 54, 55, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78 or 80 mg / day administered in 1, 2, 3, 4, 5 or 6 aliquots. In some embodiments, the aliquots are substantially equivalent in volume. In some embodiments, the volumes of the aliquots (e.g., "sprays") are 25 μ? at 150 μ ?, for example, 25 μ? at 100 μ ?, 30 μ? at 80 μ ?, 40 μ? at 75 μ? . In some embodiments, the volumes of the aliquots are 25-60 μ ?, 30-70 μ ?, 40-60 μ ?, 50-90 μ? or 60-80 μ? . In some embodiments, the volumes of the aliquots are 20 μ ?, 22 μ ?, 24 μ ?, 25 μ ?, 26 μ ?, 28 μ ?, 30 μ ?, 32 μ ?, 34 μ? , 35 μ ?, 36 μ ?, 38 μ ?, 40 μ ?, 42, μ ?, 44 μ ?, 45 μ ?, 46 μ ?, 48 μ ?, 50 μ ?, 55 μ ?, 54 μ ?, 55 μ ?, 56 μ ?, 58 μ ?, 60 μ ?, 62 μ ?, 64 μ ?, 65 μ ?, 66 μ ?, 68 μ ?, 70 μ ?, 72 μ ?, 74 μ ?, 75 μ ?, 76 μ ?, 78 μ ?, 80 μ ?, 82 μ ?, 84 μ ?, 85 μ ?, 86 μ ?, 88 μ ?, 90 μ ?, 92 μ? , 94 μ ?, 95 μ ?, 96 μ ?, 98 μ? or 100 μ? . In some embodiments, the total effective daily dose is 40 mg / day of metoclopramide base or 56 mg / day of metoclopramide base administered in four aliquots (4x50 μm or 4x70 μm) throughout the day. In some embodiments, the total effective daily dose is 80 mg / day of metoclopramide base administered in 8 aliquots (one in each nostril, four times throughout the course of the day).

In some embodiments, the method comprises the treatment of symptoms associated with female gastroparesis of variable etiology, which includes female gastroparesis arising from, associated with or caused by diabetes (including type 1 and type 2), post-viral syndromes, anorexia nervosa, surgery in the stomach or the vagus nerve, medications such as anticholinergic and narcotic medications, which tend to suppress intestinal and gastroesophageal contractions, gastroesophageal reflux disease, smooth muscle disorders (eg, amyloidosis and scleroderma), nervous system diseases (including migraine) abdominal and Parkinson's disease) and / or metabolic disorders (including hypothyroidism).

In some embodiments, gastroparesis is of diabetic origin, which includes type 1 and type 2 diabetes, and the treatment comprises intranasally administering a nasal composition of metoclopramide as described herein in a nasal spray dosage form for about 1 hour. about 8 weeks, for about 2 weeks to about 8 weeks or for 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.

The administration can be prescribed 30 minutes before meals, assuming 3 meals a day, and before going to bed. In some embodiments, the doses are administered before breakfast and dinner. In some embodiments, each dose is administered as a single intranasal aliquot (e.g., spray); in some embodiments, each dose is administered as 2 aliquots (e.g., a nasal spray).

In some embodiments, a pharmaceutical composition administered for the treatment of symptoms associated with female gastroparesis as described herein consists of: metoclopramide (e.g., as HC1 of metoclopramide), citric acid (e.g., as the monohydrate), sodium citrate (for example, as the dihydrate), benzalkonium chloride (for example, as a 50% solution, N.F.), sorbitol (for example, as a solution, such as a 70% USP solution), disodium edetate, sodium chloride and purified water. In some embodiments, a pharmaceutical composition administered for the treatment of female gastroparesis consists of: metoclopramide (e.g., as HC1 of metoclopramide), citric acid (e.g., as the monohydrate), sodium citrate (e.g., as the dihydrate ), benzalkonium chloride (for example, as a 50% solution, NF), disodium edetate, sodium chloride and purified water. In some embodiments, a pharmaceutical composition administered for the treatment of female gastroparesis consists of: metoclopramide (e.g., as HC1 of metoclopramide), citric acid (e.g., as the monohydrate), sodium citrate (e.g., as the dihydrate ), benzalkonium chloride (for example, as a 50% solution, NF), sodium chloride and purified water.

The nasal metoclopramide compositions described herein can be administered to a female patient as a spray in a single nostril, four times a day (1 spray four times a day for about 1, 2, 3, 4, 5, 6, 7 or 8 weeks), or 1 spray per nostril in both nostrils four times a day (2 sprays four times a day for approximately 1, 2, 3, 4, 5, 6, 7 or 8 weeks).

In some embodiments, the nasal metoclopramide is administered in the absence of other medications for gastroparesis. In some embodiments, additional medication may be administered if necessary. In some embodiments, the methods of treatment provided herein may also include co-administration of one or more additional therapeutic agents in conjunction with the nasal metoclopramide formulations described herein. Additional therapeutic agents are administered simultaneously with metoclopramide or at separate time intervals. In some embodiments, one or more other drugs may be incorporated into the nasal metoclopramide formulation. Additional therapeutic agents may include analgesics, insulin and other drugs useful in the control of diabetes, spheroids, especially spheroids that prevent nasal irritation, and antidepressants.

Various techniques can be used to assess the severity of gastroparesis and gastric emptying, and these will be well known to those skilled in the art. Such techniques include asking the patient about the symptoms of gastroparesis by a measuring instrument. symptoms of results reported by the patient (PRO). Techniques such as the octanoic respiration test, wireless capsule endoscopy, radioscintigraphy, ultrasonography and X-rays can be used using radiopaque markers such as barium.

In some embodiments, a clinician will prescribe a lower dosage of metoclopramide because of an underlying medical condition or other clinical consideration. For example, in the case of renal insufficiency, the clinician will prescribe a dose that is appropriate for the degree of renal insufficiency or another reason for slower metabolism or elimination of metoclopramide, for example, a dose that is 25% at 75% lower, in some embodiments 50% lower, than the dose prescribed for a patient without renal failure. In some such embodiments, the daily dose will be 20 mg administered as two intranasal doses, for example, one dose before breakfast and one before dinner. In some embodiments, each dose is administered as a single intranasal aliquot (e.g., spray). In some embodiments, each dose is administered as two intranasal aliquots (e.g., 2 sprays, one in each nostril).

The aforementioned dosages for the treatment and control of gastroparesis can be administered before meals and / or before going to bed. In some embodiments, each dose is administered as a single intranasal aliquot (eg, 1 spray in a nostril); in some embodiments, the dose can be fractionated into 2 or more intranasal aliquots (e.g., 2 sprays, one in each nostril).

Manufacture of other formulations Some embodiments of the invention comprise the administration of oral, buccal, sublingual, pulmonary, topical, transdermal, rectal or intravenous metoclopramide.

Metoclopramide can be administered orally. Suitable oral dosage forms include swallow tablets, capsules, powders and liquids. Suitable oral dosage forms also include oral disintegrating tablets, soft gel capsules that release fluid into the mouth. Metoclopramide is available as an oral liquid and can be obtained from various commercial sources, such as Wockhardt ba or the name metoclopramide hydrochloride as described in the summarized new drug application ANDA074703. Metoclopramide is also commercially available as an oral disintegrating tablet such as Metozolv® ODT from Salix Pharmaceuticals, Inc., as described in the new drug application NDA022246, and U.S. Patent No. 6,413,549, which is incorporated in this document by reference in its entirety. Metoclopramide is also commercially available as an oral tablet (for swallowing) as Reglan® from ANI Pharmaceuticals, Inc., as described in the new drug application NDA017854.

Metoclopramide can be administered buccally or sublingually. Suitable buccal forms include tablets, patches and films that are applied to the buccal surface and absorbed transcutaneously. Oral tablets are described in, inter alia, United States Patent Nos. 7,651,698; 7,122,198; 6,916,485; 5,888,534; and 5,624,677. Oral patches are described in, inter alia, United States Patent No. 6,197,331. Sublingual forms include tablets and films, such as those described in United States Patent Nos. 6,974,590; 6,572,891; 6,200,604; 5,888,534; and 5,624,677. Each of the above patents is incorporated herein by reference in its entirety.

Metoclopramide can be administered by pulmonary inhalation. Metoclopramide can be administered as a dry powder, as a metered dose of a metered dose inhaler, or as a nebulized form of a nebulizer.

Metoclopramide can also be administered by topical or transdermal means. For transdermal administration, the Metoclopramide can be formulated into ointments, ointments, gels or creams as are generally known in the art.

Metoclopramide can also be administered by intravenous administration. Intravenous metoclopramide is approved by the American Medicines Agency and is available from Baxter Healthcare Corp. under the brand name REGLAN®. The intravenous solution is described in the application for new drug NDA017862.

Examples Example 1: A multicenter, randomized, double-blind, placebo-controlled, parallel dose-determination study to evaluate the efficacy and safety of metoclopramide nasal spray solution in diabetic subjects with gastroparesis The objectives of this study were to evaluate the safety and efficacy of two doses of nasal spray solution of metoclopramide, 10 mg and 14 mg, compared with placebo in reducing the symptoms of diabetic gastroparesis and evaluating the plasma concentrations of two doses of metoclopramide nasal spray in subjects with diabetic gastroparesis after a single dose and in a steady state. The aforementioned dosages for the treatment and control of gastroparesis were administered before meals and / or before going to hospital. bed. Those who meet the entry criteria after the washout period (day -7 to day -1) were randomized using an IVRS nasal spray of metoclopramide 10 mg, 14 mg, or placebo, in roughly equal numbers (approximately 1 : 1: 1) using a predetermined scrambling program that uses permuted blocks. Randomization was performed centrally.

The nasal spray solution of metoclopramide, 200 mg / ml base (as monohydrochloride monohydrate), is a clear to pale yellow colorless aqueous solution manufactured by Evoke Pharma. The nasal spray of metoclopramide was packaged in a 10 ml amber glass vial mounted with a dosed nasal spray pump. The measured dose vial released a 50 μ? Spray. or 70 μ? (10 mg or 14 mg of metoclopramide base, respectively) with each performance. One vial of 10 ml contained enough nasal spray of metoclopramide to administer 120 doses of 10 mg or 14 mg.

A vehicle control was used as a placebo for the nasal spray solution of metoclopramide. The placebo spray was packaged in a 10 ml amber glass vial mounted with a dosed nasal spray pump. The measured dose vial released a 50 μ? Spray. with each performance. A vial of 10 ml contained enough placebo to administer 120 doses. The administration of both a spray of 50 μ? How about 70 μ? it is indistinguishable for the subject or study staff.

A washout period of 7 days preceded randomization. During this time, and for the duration of the study, subjects were asked to suspend the use of all medications that are known to improve or aggravate symptoms associated with diabetic gastroparesis. Subjects were instructed on the use of an interactive voice response system (IVRS) to record the severity of nine gastrointestinal symptoms of GCSI-DD and additional symptoms such as: severity of abdominal pain and abdominal discomfort, number of hours of nausea , number of episodes of vomiting and general severity of gastroparesis symptoms in a daily agenda. The IVRS was used during the treatment period for self-reported evaluations. The subjects completed these agenda evaluations through the IVRS every afternoon.

After the washout period, subjects who met all entry criteria and had an average daily score of > 2 a = 4 during the 7-day washout period in the GCSI-DD of nine symptoms were randomized on day 0 to one of the three treatment groups to receive both 10 mg or 14 mg metoclopramide nasal spray and placebo, a spraying in any nostril, four times a day, 30 minutes before meals and going to sleep. Your scores with a total GCSI-DD average score of < 2.0 or > 4.0 during the 7-day washout period were excluded from the study.

At the randomization visit (day 0), the questionnaire for the evaluation of patients with symptoms of upper gastrointestinal disorders (PAGI-SYM), and the disability questionnaires, were administered to the subject and the researcher and the subject evaluated the overall severity of the the symptoms of gastroparesis (OGS) before taking the study drug. Subjects started taking the study drug at the clinical site with a single dose on day 0. Subjects returned to the clinic for safety and efficacy evaluations at visits 4, 5, 6 and 7 (days 7, 14, 21 and 28).

At each study visit programmed to the clinical site of the study, compliance with the daily agenda of the IVRS was reviewed. In addition, at visit 5 (day 14), the PAGI-SYM questionnaire was administered to the subject and the investigator and the subject evaluated the severity of OGS. At the final visit (day 28) subjects took their last dose of the study drug at the clinical site and returned their unused / remaining study drug vial. The subject completed the PAGI-SYM and disability questionnaires. The investigator and the subject evaluated OGS and the overall treatment effect (OTE).

The study drug was administered intranasally (a spray in either the right or left nostril) four times a day, 30 minutes before meals and when going to sleep. The subjects were instructed on the correct use of the nasal spray, were reminded not to exceed a total of four sprays per day and received their first and last dose of study drug in the clinic on day 0 and day 28.

Pharmacokinetic blood samples (PK) for determination of metoclopramide concentration were obtained from all subjects at visit 3, day 0 (before the dose and 30 minutes after dosing [single dose]) and at the visit final (day 28) 30 minutes after the dose (steady state).

The main measure of effectiveness for this study was the change in the total index score of the cardinal symptom of modified mean gastroparesis -Daily index (mGCSI-DD) from the initial level of 7 days (day -7 to day -1) until the last 7 days (day 21 to day 28 for subjects who complete 28 days of treatment) of the treatment period between each of the two active treatment groups and the placebo group. The mGCSI-DD, a The evaluation informed by the severity of gastroparesis symptoms will be the instrument used during the washout period (initial level) and the dosing phase of the study to record daily symptoms. The daily agenda scores were recorded using an interactive voice response system (IVRS) at the same time each afternoon.

The mGCSI-DD was chosen for this study because the instrument was developed specifically to capture the symptoms of gastroparesis and has been tested in its etiology with diabetic gastroparesis. The range of mean GCSI-DD scores selected for inclusion in the study was based on the severity of gastroparesis symptoms. Subjects with an average GCSI-DD score of < 2.0 are considered to have very mild symptoms while subjects with a mean GCSI-DD score > 4.0 are considered to have symptoms of severe to very severe more appropriately treated by parenteral metoclopramide.

The study consisted of a 23-day selection period, a 7-day washout period (day -7 to day -1) followed by four weeks of treatment with the study drug. The total duration of each subject's participation was approximately 8 weeks. 287 subjects were enrolled in the study and the following groups were randomized: Placebo (n = 95), intranasal 10 mg (n = 96) and intranasal 14 mg (n = 96). Of those subjects enrolled, a total of 259 completed the study (-90%). There were no dose-limiting toxicities and no reports of tardive dyskinesia. Of the study subjects who did not complete the item, 4 were from the placebo group, 3 from the 10 mg IN group and 8 from the 14 mg IN group.

Daily diary of symptoms Test subjects were asked daily questions about their symptoms of gastroparesis. The daily agenda was completed every afternoon. For each symptom, the subjects were instructed to choose the number (0-5) that best described how severe the symptom had been the previous 24 hours. The subjects were instructed to answer each question. The following symptom scores were used: 0 = None; l = Very slight; 2 = Mild; 3 = Moderate; 4 = Serious; 5 = Very serious. The IVRS asked each subject about the following symptoms: 1. Nausea (feeling sick in the stomach as if going to vomit); 2. Effort to vomit (have gagging as if he were going to vomit, but nothing is achieved); 3. Vomiting; 4. Fullness of the stomach; 5. You can not finish a normal-sized meal; 6. Excessively full feeling after meals; 7. Loss of appetite; 8. Meteorism; 9. Visibly greater stomach or belly; 10. Upper abdominal pain (above the navel); 11. Abdominal discomfort superior (above the navel). The test subjects were asked the following question: "How has today been the general severity of your gastroparesis symptoms (during the previous 24 hours)?" "During the previous 24 hours, how many episodes of vomiting did you have?" and "During the previous 24 hours, how many hours of nausea did you have?" Questionnaire for the evaluation of patients with symptoms of upper gastrointestinal disorders (PAGI-SYM) This questionnaire asked the students about the severity of symptoms related to their gastrointestinal problems. For each symptom, subjects were instructed to select the number that best described how severe the symptom had been during the previous 2 weeks. If the subject did not experience this symptom, he had to select 0. If the symptom was mild, the subject was instructed to select 1. If moderate, the subject was instructed to select 3. If it was severe, the subject was instructed to select 4. If it was very serious, the subject was instructed to select 5. The subjects were instructed to answer each question as accurately as possible, and to answer each question. The symptoms that the subjects scored were: 1. Nausea (feeling sick in the stomach as if going to vomit); 2. Effort to vomit (have gagging as if he were going to vomit, but do not get to nothing); 3. Vomiting; 4. Fullness of the stomach; 5. You can not finish a normal-sized meal; 6. Excessively full feeling after meals; 7. Loss of appetite; 8. Meteorism (feeling that you need to loosen your clothes); 9. Visibly greater stomach or belly; 10. Upper abdominal pain (above the navel); 11. Upper abdominal discomfort (below the navel); 12. Lower abdominal pain (below the navel); 13. Lower abdominal discomfort (below the navel); 14. Heartburn during the day (burning that goes up through the chest or throat); 15. Heartburn when lying down (burning up the chest or throat); 16. Sensation of discomfort inside the chest during the day; 17. Sensation of discomfort inside the chest at night (during the time of sleep); 18. Regurgitation or reflux during the day (fluid or liquid from the stomach goes up into the throat); 19. Regurgitation or reflux when lying down (fluid or liquid from the stomach goes up the throat); 20. Bitter, acid or sour taste in the mouth.

Main criterion of effectiveness assessment - ITT: Change of reference level to week 4 in mGCSI-DD average. The following table summarizes mGCSI-DD scores for all subjects (ie, without sex differentiation) for placebo, subject groups of 10 mg IN and 14 mg IN (treatment arms). As can be seen from the paired p-values, no treatment arm experienced a statistically significant improvement in the mGCSI-DD score over placebo.

Main criterion of effectiveness assessment - ITT - By sex: Changes from the initial level to week 4 in mGCSI-DD average for women (men). When the subjects were classified by sex (as previously specified in the statistical analysis plan) there was a clear difference in mGCSI-DD scores between women and men. As can be seen in the p values in the following table, women in both the 10 mg IN and 14 mg IN groups (treatment arms) experienced a statistically significant improvement in mGCSI-DD scores versus placebo, but did not the men in both arms of treatment.

Main and secondary criteria for assessment by sex in week 4. The following table summarizes the results (A = Active favors, P = Favors placebo) for the main endpoint (mGCSI-DD score) and secondary endpoints of the study. . As can be seen in the table, in women of both treatment arms (10 mg and 14 mg), the results of the mGCSI-DD score and the various secondary endpoints favor the active (intranasal metoclopramide). In contrast, in men with both treatment arms, mGCSI-DD scores favored placebo, as did each secondary endpoint other than vomiting.

Exploratory criteria for assessment by sex in week 4. The study also followed several exploratory assessment criteria. The following table summarizes the results (A = Active favors, P = Favors placebo) for the main endpoint (mGCSI-DD score) and the study's exploratory criteria. As can be seen in the table, in many of both arms of treatment (10 mg and 14 mg) favor the active (intranasal metoclopramide) according to the GCSI-DD score. Likewise, according to women, they favored assets for most of the exploratory valuation criteria. In contrast, in men with both treatment arms, GCSI-DD scores favored placebo, as did most of the exploratory endpoints.

Demography of the eto - ITT: The following table shows that the dose groups are comparable through multiple characteristics, including GCSI-DD average of the initial level and mGCSI-DD METO-IN-002: Characteristics of demography and initial level (population of ITT) Subject demography - ITT by sex (M / F): The following table shows that there were no sex-based differences in the demographic or symptom scores at the initial level.

METO-IN-002: Demographic characteristics and the initial key level by sex (population of ITT) The statistical analysis of the data interaction test of the upper line showed the interaction between treatment, sex and the main endpoint - Change of mGCSI-DD from baseline to week 4 is significantly different between men compared to women (p = 0.0381). As can be seen in the following table, the effects of treatment appear opposite in men and women. [1] Initial level is defined as the total mGCSI-DD average score during the washout period [2] The values of p for matched comparisons are obtained from an ANCOVA model with effects for the treatment group and value of the initial level as a covariate. [3] The value of p for sex through the interaction test with the treatment is obtained from a model of ANCOVA with effects for the treatment group, sex, treatment by sex interaction and value of the initial level as a covariate.

Results for mGCSI-DD key symptoms: Nausea, bloating, early satiety and abdominal pain Pharmacokinetics: The pharmacokinetics (P) of the study drug was evaluated in all subjects. Figure 1 summarizes PK data (blood plasma concentration of metoclopramide in ng / ml) for both treatment arms (10 mg and 14 mg, intranasal) at visit 3 and visit 7. Individual data are represented by circles and the The arithmetic mean and geometric mean of each group is represented by lines (in each case, the upper line represents the arithmetic mean and the lower line represents the geometric mean). In Figure 2, the PK data are analyzed by sex. As in Figure 1, the circles represent individual data, while the lines represent means (upper line = arithmetic mean, lower line = geometric mean.) As can be seen in Figure 2, the PK data for men and women were similar, when compared to similar dosages in the same days. The statistical analysis revealed that any obvious difference in mean values between women and men was not statistically significant.

Summary of phase 2: As can be seen in the tables above, for female subjects, 11 of the 11 symptoms for which data were collected had statistical separation or improved trends compared to placebo (p = 0.001). In contrast, male subjects only had 1 of 11 symptoms that showed a positive trend (p = 0.0118). These differences can not be rationalized based on differences in pharmacokinetics between men and women, since no statistical difference in P values was observed as observed between women and men in any treatment arm (10 mg, 14 mg) in any of the days (visit 3, visit 7) tested. The similarity in PK data between the two sex groups suggests that it is unlikely that the difference in efficacy can be explained as a difference in relative dosage. Thus, it is not evident from these results that increasing the dose in men will enhance efficacy in this group. There were no obvious demographic differences between women and men that explained the difference in efficacy between the two groups. From these results it is reasonable to deduce that the Intranasal metoclopramide is effective in the treatment of female gastroparesis, but not male gastroparesis. At least, it is reasonable to conclude that at the doses studied - 10 mg and 14 mg - intranasal metoclopramide is effective for the treatment of symptoms associated with female diabetic gastroparesis, but not in the treatment of symptoms associated with male diabetic gastroparesis .

Figures 3 and 4 graphically represent the total mGCSI-DD mean scores at the initial level and the change from the initial level to week 4 in female and male subjects, respectively. As can be seen in these graphs, the female subjects experienced statistically significant improvement in mGCSI-DD from the initial level to both 10 mg and 14 mg of dose (corresponding to 40 mg and 56 mg daily doses, respectively), while male subjects they did not experience significant improvement.

Although preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will now occur for those skilled in the art without depart from the invention. It should be understood that the various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. The following claims are intended to define the scope of the invention and that the procedures and structures within the scope of these claims and their equivalents are thus covered.

Claims

NOVELTY OF THE INVENTION Having described the invention as above, it is considered as a novelty and, therefore, is claimed as property contained in the following: CLAIMS

1. - Use of metoclopramide, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating symptoms of gastroparesis in a female human being.

2. The use of claim 1, wherein the medicament is formulated for oral, buccal, sublingual, intranasal, pulmonary, topical, transdermal, rectal or intravenous administration.

3. The use of claim 1, wherein the medicament is formulated for intranasal administration.

4. The use of claim 1, 2 or 3, wherein the medicament is ineffective for treating male gastroparesis.

5. The use of claim 1, 2, 3 or 4, wherein the metoclopramide is administered at a daily dose of about 20 mg to 100 mg of metoclopramide base per day.

6. - The use of any one of claims 1-5, wherein the symptom of gastroparesis is one or more symptoms selected from the group consisting of associated upper abdominal pain, nausea, bloating, early satiety, vomiting, straining for vomiting, feeling full (inability to finish a meal), loss of appetite, fullness of stomach, stomach It is visibly larger, upper abdominal discomfort.